This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aghi, M. Articles by Chiocca, E. A. Search for Related Content PubMed PubMed Citation Articles by Aghi, M. Articles by Chiocca, E. A.

Multimodal Cancer Treatment Mediated by a Replicating Oncolytic Virus That Delivers the Oxazaphosphorine/Rat Cytochrome P450 2B1 and Ganciclovir/Herpes Simplex Virus Thymidine Kinase Gene Therapies¹

Molecular Neuro-Oncology Laboratories, Neurosurgical Service [M. A., K. S., E. A. C.], and Molecular Neurogenetics Unit [X. O. B.], Massachusetts General Hospital, Boston, Massachusetts 02114; and Molecular Pharmacology and Therapeutic Program, Memorial Sloan-Kettering Cancer Center and Cornell University, Graduate School of Medical Sciences, New York, New York 10001 [T. C. C.]

Multimodal therapy is generally more effective than single-agent treatment for cancer. rRp450 is an engineered herpes simplex viral mutant that replicates in and kills tumor cells in a relatively selective fashion. It also expresses, in infected cells, the cyclophosphamide (CPA)-sensitive rat cytochrome P450 2B1 (CYP2B1) and the ganciclovir (GCV)-sensitive herpes simplex virus thymidine kinase (HSV-TK) transgenes. We show that cultured rat 9L and human U87EGFR glioma cells, infected and lysed by rRp450, also exhibit supra-additive sensitivity to both CPA and GCV, as determined by Chou-Talalay synergy analysis. DNA cross-linking, assayed by ethidium bromide fluorescence, was significantly inhibited in the presence of GCV, suggesting that interactions between the CPA/CYP2B1 and GCV/HSV-TK gene therapies occurred at the level of DNA repair. In vivo, regression of 9L s.c. tumor volumes in athymic mice was achieved only by the multimodal treatment allowed by rRp450 viral oncolysis combined with CPA/CYP2B1 and GCV/HSV-TK gene therapies, whereas all other treatment combinations produced only tumor growth retardation.

This article has been cited by other articles:

				T.-C. Liu, T. Zhang, H. Fukuhara, T. Kuroda, T. Todo, X. Canron, A. Bikfalvi, R. L. Martuza, A. Kurtz, and S. D. Rabkin Dominant-Negative Fibroblast Growth Factor Receptor Expression Enhances Antitumoral Potency of Oncolytic Herpes Simplex Virus in Neural Tumors. Clin. Cancer Res., November 15, 2006; 12(22): 6791 - 6799. [Abstract] [Full Text] [PDF]

				T.-C. Chou Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies Pharmacol. Rev., September 1, 2006; 58(3): 621 - 681. [Abstract] [Full Text] [PDF]

				A. Friedman, J. P. Tian, G. Fulci, E. A. Chiocca, and J. Wang Glioma Virotherapy: Effects of Innate Immune Suppression and Increased Viral Replication Capacity Cancer Res., February 15, 2006; 66(4): 2314 - 2319. [Abstract] [Full Text] [PDF]

				M. L.M. Lamfers, D. Gianni, C.-H. Tung, S. Idema, F. H.E. Schagen, J. E. Carette, P. H.A. Quax, V. W. Van Beusechem, W. P. Vandertop, C. M.F. Dirven, et al. Tissue Inhibitor of Metalloproteinase-3 Expression from an Oncolytic Adenovirus Inhibits Matrix Metalloproteinase Activity In vivo without Affecting Antitumor Efficacy in Malignant Glioma Cancer Res., October 15, 2005; 65(20): 9398 - 9405. [Abstract] [Full Text] [PDF]

				D. S. Riddick, C. Lee, S. Ramji, E. C. Chinje, R. L. Cowen, K. J. Williams, A. V. Patterson, I. J. Stratford, C. S. Morrow, A. J. Townsend, et al. CANCER CHEMOTHERAPY AND DRUG METABOLISM Drug Metab. Dispos., August 1, 2005; 33(8): 1083 - 1096. [Abstract] [Full Text] [PDF]

				E. Tyminski, S. LeRoy, K. Terada, D. M. Finkelstein, J. L. Hyatt, M. K. Danks, P. M. Potter, Y. Saeki, and E. A. Chiocca Brain Tumor Oncolysis with Replication-Conditional Herpes Simplex Virus Type 1 Expressing the Prodrug-Activating Genes, CYP2B1 and Secreted Human Intestinal Carboxylesterase, in Combination with Cyclophosphamide and Irinotecan Cancer Res., August 1, 2005; 65(15): 6850 - 6857. [Abstract] [Full Text] [PDF]

				E. A. Chiocca Oncolytic Viral Therapeutics Based on Herpes Simplex Virus Type I Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 139 - 140. [Full Text] [PDF]

				E. Seo, M. Abei, M. Wakayama, K. Fukuda, H. Ugai, T. Murata, T. Todoroki, Y. Matsuzaki, N. Tanaka, H. Hamada, et al. Effective Gene Therapy of Biliary Tract Cancers by a Conditionally Replicative Adenovirus Expressing Uracil Phosphoribosyltransferase: Significance of Timing of 5-Fluorouracil Administration Cancer Res., January 15, 2005; 65(2): 546 - 552. [Abstract] [Full Text] [PDF]

				R. L. Chu, D. E. Post, F. R. Khuri, and E. G. Van Meir Use of Replicating Oncolytic Adenoviruses in Combination Therapy for Cancer Clin. Cancer Res., August 15, 2004; 10(16): 5299 - 5312. [Abstract] [Full Text] [PDF]

				D. J. Waxman and P. S. Schwartz Harnessing Apoptosis for Improved Anticancer Gene Therapy Cancer Res., December 15, 2003; 63(24): 8563 - 8572. [Abstract] [Full Text] [PDF]

				J. T. Mullen and K. K. Tanabe Viral Oncolysis Oncologist, April 1, 2002; 7(2): 106 - 119. [Abstract] [Full Text] [PDF]

				C. J. A. Ring Cytolytic viruses as potential anti-cancer agents J. Gen. Virol., March 1, 2002; 83(3): 491 - 502. [Abstract] [Full Text] [PDF]

				T. Ichikawa and E. A. Chiocca Comparative Analyses of Transgene Delivery and Expression in Tumors Inoculated with a Replication-conditional or -defective Viral Vector Cancer Res., July 1, 2001; 61(14): 5336 - 5339. [Abstract] [Full Text] [PDF]

				Y. Jounaidi and D. J. Waxman Frequent, Moderate-Dose Cyclophosphamide Administration Improves the Efficacy of Cytochrome P-450/Cytochrome P-450 Reductase-based Cancer Gene Therapy Cancer Res., June 1, 2001; 61(11): 4437 - 4444. [Abstract] [Full Text] [PDF]

				P. Y.P. Lam and X. O. Breakefield Potential of gene therapy for brain tumors Hum. Mol. Genet., April 1, 2001; 10(7): 777 - 787. [Abstract] [Full Text] [PDF]

				A. Jacobs, J. G. Tjuvajev, M. Dubrovin, T. Akhurst, J. Balatoni, B. Beattie, R. Joshi, R. Finn, S. M. Larson, U. Herrlinger, et al. Positron Emission Tomography-based Imaging of Transgene Expression Mediated by Replication-conditional, Oncolytic Herpes Simplex Virus Type 1 Mutant Vectors in Vivo Cancer Res., April 1, 2001; 61(7): 2983 - 2995. [Abstract] [Full Text]

				T. Ichikawa, W. P. Petros, S. M. Ludeman, J. Fangmeier, F. H. Hochberg, O. M. Colvin, and E. A. Chiocca Intraneoplastic Polymer-based Delivery of Cyclophosphamide for Intratumoral Bioconversion by a Replicating Oncolytic Viral Vector Cancer Res., February 1, 2001; 61(3): 864 - 868. [Abstract] [Full Text]

				N. Ariyoshi, S. Imaoka, K. Nakayama, Y. Takahashi, K.-I. Fujita, Y. Funae, and T. Kamataki Comparison of the Levels of Enzymes Involved in Drug Metabolism between Transgenic or Gene-knockout and the Parental Mice Toxicol Pathol, January 1, 2001; 29(1_suppl): 161 - 172. [Abstract] [PDF]

				T. M. Pawlik, H. Nakamura, S. S. Yoon, J. T. Mullen, S. Chandrasekhar, E. A. Chiocca, and K. K. Tanabe Oncolysis of Diffuse Hepatocellular Carcinoma by Intravascular Administration of a Replication-competent, Genetically Engineered Herpesvirus Cancer Res., June 1, 2000; 60(11): 2790 - 2795. [Abstract] [Full Text] [PDF]

				K. Ikeda, H. Wakimoto, T. Ichikawa, S. Jhung, F. H. Hochberg, D. N. Louis, and E. A. Chiocca Complement Depletion Facilitates the Infection of Multiple Brain Tumors by an Intravascular, Replication-Conditional Herpes Simplex Virus Mutant J. Virol., May 15, 2000; 74(10): 4765 - 4775. [Abstract] [Full Text]